Associations Between Neuroinflammation-Related Conditions and Alzheimer's Disease: A Study of US Insurance Claims Data.

Background: Early detection of Alzheimer's disease (AD) is a key component for the success of the recently approved lecanemab and aducanumab. Patients with neuroinflammation-related conditions are associated with a higher risk for developing AD. Objective: Investigate the incidence of AD among patients with neuroinflammation-related conditions including epilepsy, hemorrhage stroke, multiple sclerosis (MS), and traumatic brain injury (TBI). Methods: We used Optum's de-identified Clinformatics Data Mart Database (CDM). We derived covariate-matched cohorts including patients with neuroinflammation-related conditions and controls without the corresponding condition. The matched cohorts were: 1) patients with epilepsy and controls (N = 67,825 matched pairs); 2) patients with hemorrhage stroke and controls (N = 81,510 matched pairs); 3) patients with MS and controls (N = 9,853 matched pairs); and 4) patients TBI and controls (N = 104,637 matched pairs). We used the Cox model to investigate the associations between neuroinflammation-related conditions and AD. Results: We identified that epilepsy, hemorrhage stroke, and TBI were associated with increased risks of AD in both males and females (hazard ratios [HRs]≥1.74, p < 0.001), as well as in gender- and race-conscious subpopulations (HRs≥1.64, p < 0.001). We identified that MS was associated with increased risks of AD in both males and females (HRs≥1.47, p≤0.004), while gender- and race-conscious subgroup analysis shown mixed associations. Conclusions: Patients with epilepsy, hemorrhage stroke, MS, and/or TBI are associated with a higher risk of developing AD. More attention on cognitive status should be given to older patients with these conditions.

Risk of Neuroinflammatory Diseases Among New Recipients of Biologic and Targeted Synthetic Disease-Modifying Antirheumatic Drugs.

OBJECTIVE: Neuroinflammatory adverse events have been observed among new users of tumor necrosis factor (TNF) inhibitors. No studies to date have compared the real-world risk of TNFs with other new users of biologic or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs). The objective of this study is to describe the risk of neuroinflammatory disease after initiation b/tsDMARDs. METHODS: This new user comparative effectiveness cohort study used a large US-based electronic health records database to describe the unadjusted incidence of neuroinflammatory adverse events over a 3-year period. The cohort included patients with rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, or ulcerative colitis initiating treatment with a TNF inhibitor (n = 93,661) or other b/tsDMARD (n = 38,354). RESULTS: Among 132,015 patients included in the analysis, the most common first biologic agent was a TNF inhibitor; the unadjusted incidence of neuroinflammatory events was numerically lower among new users of TNF inhibitors (incidence 1.34 per 1,000 patient-years) as compared with the combined non-TNF group (1.69 per 1,000 patient-years). There was no significant association between TNF exposure and neuroinflammatory events as compared with the combined non-TNF b/tsDMARDs overall (hazard ratio 1.01; 95% confidence interval 0.75-1.36) and within each disease group. CONCLUSION: The overall risk of neuroinflammatory events among new users of TNF inhibitors did not differ substantially as compared with new users of other b/tsDMARDs. Meta-analyses of randomized trials should be conducted to corroborate these findings, which may be affected by channeling bias.

Factores de riesgo que contribuyen a la neuroinflamación crónica y disfunción cerebral / Risk factors that contribute to chronic neuro-inflammation and brain dysfunction

El estilo de vida saludable conlleva un comportamiento adaptable, que es fundamental para la salud mental del hombre e incluye aspectos relacionados con los factores ambientales. La revisión tuvo como objetivo mostrar los avances en las investigaciones sobre los factores de riesgo que contribuyen a la neuroinflamación crónica, sus efectos a nivel cerebral, así como el papel de un estilo de vida saludable en promover la neuroplasticidad. Para ello se realizaron búsquedas principalmente en la base de datos PubMed, y como resultado, se confirmó una asociación positiva entre los estados inflamatorios subclínicos surgidos de estilos de vida poco saludables, y la neuroinflamación crónica con la consecuente neurodegeneración. Lo anterior derivó como conclusión que algunos factores de riesgo como la dieta poco saludable, la obesidad, el estrés, la depresión, la falta de ejercicio físico y los desórdenes del ciclo circadiano son factores conductuales modificables, que deben ser objeto de atención y solución, tanto en lo individual como en lo social. Todo ello resulta un aspecto preocupante en el tema de las enfermedades neurodegenerativas y su enorme costo para la sociedad futura(AU)

A healthy lifestyle involves adaptive behavior, which is fundamental for men's mental health, and includes aspects related to the environmental factors. The review aimed to show advances in research on the risk factors that contribute to chronic neuro-inflammation, its effects at the brain level, as well as the role of a healthy lifestyle in promoting neuroplasticity. For this purpose, searches were carried out mainly in the PubMed database, and as a result, a positive association was confirmed between subclinical inflammatory states arising from unhealthy lifestyles, and chronic neuro-inflammation with consequent neuro-degeneration. The above led to the conclusion that some risk factors such as unhealthy diet, obesity, stress, depression, lack of physical exercise, and circadian cycle disorders are modifiable behavioral factors, which should be the object of attention and solution, both individually and socially. All of this is a worrying aspect of the issue of neurodegenerative diseases and their enormous cost for future society(AU)

Targeting neuroinflammation by polyphenols: A promising therapeutic approach against inflammation-associated depression.

Depression is the most prevalent and debilitating mental disorder that affects a substantial number of people globally, hindering all aspects of their lives and leading to a high number of suicides each year. Despite the availability of an array of antidepressant medications, taking these medications does not relieve depressive symptoms in a considerable number of patients, implying that an incomplete understanding of the pathomechanisms involved in the development of depression. Besides that, a subset of those non-responsive patients exhibits an increased systemic and central inflammatory response, which has collectively led to the evolvement of the inflammatory theory of depression. Indeed, peripherally generated inflammatory mediators, as well as insults within the brain, can activate the brain's resident immune cells, resulting in a neuroinflammatory response that interferes with the multitude of neurobiological domains implicated in the pathogenesis of depression. Polyphenols, a group of plant-derived bioactive molecules, have been shown to exert neuroprotective functions on the brain by influencing an array of neuropathological mechanisms, including neuroinflammation. From these perspectives, this review mechanistically provides an overview of the neuropathological roles of sustained neuroinflammatory response in the development of depression and elucidates the therapeutic potential of flavonoid and nonflavonoid polyphenols in modulating inflammatory mediators and signaling cascades as well as promoting other neurophysiological and neuroprotective functions underlying inflammation-associated depressive symptoms. Therefore, given their significant anti-neuroinflammatory effects, polyphenols could be a promising and effective adjunctive therapy for the treatment of neuropsychiatric symptoms associated with inflammation-related depression.

Understanding the Connection Between Common Stroke Comorbidities, Their Associated Inflammation, and the Course of the Cerebral Ischemia/Reperfusion Cascade.

Despite the enormous progress in the understanding of the course of the ischemic stroke over the last few decades, a therapy that effectively protects neurovascular units (NVUs) and significantly improves neurological functions in stroke patients has still not been achieved. The reasons for this state are unclear, but it is obvious that the cerebral ischemia and reperfusion cascade is a highly complex phenomenon, which includes the intense neuroinflammatory processes, and comorbid stroke risk factors strongly worsen stroke outcomes and likely make a substantial contribution to the pathophysiology of the ischemia/reperfusion, enhancing difficulties in searching of successful treatment. Common concomitant stroke risk factors (arterial hypertension, diabetes mellitus and hyperlipidemia) strongly drive inflammatory processes during cerebral ischemia/reperfusion; because these factors are often present for a long time before a stroke, causing low-grade background inflammation in the brain, and already initially disrupting the proper functions of NVUs. Broad consideration of this situation in basic research may prove to be crucial for the success of future clinical trials of neuroprotection, vasculoprotection and immunomodulation in stroke. This review focuses on the mechanism by which coexisting common risk factors for stroke intertwine in cerebral ischemic/reperfusion cascade and the dysfunction and disintegration of NVUs through inflammatory processes, principally activation of pattern recognition receptors, alterations in the expression of adhesion molecules and the subsequent pathophysiological consequences.

Sleep Disruption Worsens Seizures: Neuroinflammation as a Potential Mechanistic Link.

Sleep disturbances, such as insomnia, obstructive sleep apnea, and daytime sleepiness, are common in people diagnosed with epilepsy. These disturbances can be attributed to nocturnal seizures, psychosocial factors, and/or the use of anti-epileptic drugs with sleep-modifying side effects. Epilepsy patients with poor sleep quality have intensified seizure frequency and disease progression compared to their well-rested counterparts. A better understanding of the complex relationship between sleep and epilepsy is needed, since approximately 20% of seizures and more than 90% of sudden unexpected deaths in epilepsy occur during sleep. Emerging studies suggest that neuroinflammation, (e.g., the CNS immune response characterized by the change in expression of inflammatory mediators and glial activation) may be a potential link between sleep deprivation and seizures. Here, we review the mechanisms by which sleep deprivation induces neuroinflammation and propose that neuroinflammation synergizes with seizure activity to worsen neurodegeneration in the epileptic brain. Additionally, we highlight the relevance of sleep interventions, often overlooked by physicians, to manage seizures, prevent epilepsy-related mortality, and improve quality of life.

Impact of COVID-19 public health measures on myelin oligodendrocyte glycoprotein IgG-associated disorders in children.

BACKGROUND: Despite better characterization of the spectrum of MOG-IgG-associated disorders (MOGAD) in children, the role of infection in its pathophysiology remains unclear. The goal of this study was to evaluate if public health measures put in place to prevent the spread of SARS-CoV-2 in March 2020 in Ontario (Canada) have been associated with a change in the incidence of MOGAD and other neuroinflammatory disorders in children. METHODOLOGY: We reviewed a single-centre cohort of children referred for a suspicion of neuroinflammatory disorder between January 2015 and March 2021. Age, date, sex, diagnosis, MOG-IgG antibodies status and detected pathogens at presentation were identified. Comparative statistical analysis was performed based on diagnosis between years and seasons using Pearson's Chi-squared test or Fisher's exact test for categorical variables and using ANOVA or Kruskal-Wallis test for continuous variables, as appropriate. We compared the post-lockdown period (March 17th, 2020, to March 31st, 2021) to previous calendar years (2015 to 2019) alone and to previous calendar years and the pre-lockdown 2020 period (January 1st, 2020, to March 16th, 2020). A p-value of < 0.05 was considered significant. Post-hoc pairwise comparisons between the post-lockdown period and previous years were performed on significant results. A false discovery rate adjustment with an adjusted p-value (q-value) < 0.05 was computed. We hypothesized that the number of new MOGAD would be significantly lower in the post-lockdown period compared to previous years due to decreased regional pathogen transmission. RESULTS: Among 491 referred cases, we identified 415 new cases of neuroinflammatory disorder between January 2015 and March 2021. The number of new neuroinflammatory disorder diagnoses did not change between years. We noted significantly fewer new MOGAD diagnoses in 2020 compared to previous years, with no MOGAD patients presenting in 2020 after the spring lockdown (q=0.0009). In addition, there were significantly fewer parainfectious neuroinflammatory cases (q=0.04) and pathogen detected (q=0.04) in the post-lockdown period. The number of new multiple sclerosis (MS) and aquaporin-4 neuromyelitis optica spectrum disorders (AQP4-NMOSD) cases remained stable despite the lockdown (q=0.185 and 0.693 respectively). INTERPRETATION: Enhanced population-based infection control strategies may have a role in modulating the incidence of MOGAD and parainfectious neuroinflammatory disorders, but not MS or AQP4-NMOSD.

Modern Look at Transverse Myelitis and Inflammatory Myelopathy: Epidemiology of the National Veterans Health Administration Population.

BACKGROUND AND OBJECTIVES: To characterize population-level data associated with transverse myelitis (TM) within the US Veterans Health Administration (VHA). METHODS: This retrospective review used VHA electronic medical record from 1999 to 2015. We analyzed prevalence, disease characteristics, modified Rankin Scale (mRS) scores, and mortality data in patients with TM based on the 2002 Diagnostic Criteria. RESULTS: We identified 4,084 patients with an International Classification of Diseases (ICD) code consistent with TM and confirmed the diagnosis in 1,001 individuals (90.7% males, median age 64.2, 67.7% Caucasian, and 31.4% smokers). The point prevalence was 7.86 cases per 100,000 people. Less than half of the cohort underwent a lumbar puncture, whereas only 31.8% had a final, disease-associated TM diagnosis. The median mRS score at symptom onset was 3 (interquartile range 2-4), which remained unchanged at follow-up, although less than half (43.2%) of the patients received corticosteroids, IVIg, or plasma exchange. Approximately one-quarter of patients (24.3%) had longitudinal extensive TM, which was associated with poorer outcomes (p = 0.002). A total of 108 patients (10.8%) died during our review (94.4% males, median age 66.5%, and 70.4% Caucasian). Mortality was associated with a higher mRS score at follow-up (OR 1.94, 95% CI, 1.57-2.40) and tobacco use (OR 1.87, 95% CI, 1.17-2.99). DISCUSSION: This national TM review highlights the relatively high prevalence of TM in a modern cohort. It also underscores the importance of a precise and thorough workup in this disabling disorder to ensure diagnostic precision and ensure optimal management for patients with TM in the future.

Cardiovascular comorbidities, inflammation, and cerebral small vessel disease.

Cerebral small vessel disease (cSVD) is the most common cause of vascular cognitive impairment and affects all levels of the brain's vasculature. Features include diverse structural and functional changes affecting small arteries and capillaries that lead to a decline in cerebral perfusion. Due to an ageing population, incidence of cSVD is continually rising. Despite its prevalence and its ability to cause multiple debilitating illnesses, such as stroke and dementia, there are currently no therapeutic strategies for the treatment of cSVD. In the healthy brain, interactions between neuronal, vascular, and inflammatory cells are required for normal functioning. When these interactions are disturbed, chronic pathological inflammation can ensue. The interplay between cSVD and inflammation has attracted much recent interest, and this review discusses chronic cardiovascular diseases, particularly hypertension, and explores how the associated inflammation may impact on the structure and function of the small arteries of the brain in cSVD. Molecular approaches in animal studies are linked to clinical outcomes in patients, and novel hypotheses regarding inflammation and cSVD are proposed that will hopefully stimulate further discussion and study in this important area.

Schizophrenia and Dental Health: A Systematic Review.

ABSTRACT: Schizophrenia is characterized not only by psychopathological symptoms but also by medical comorbidities. Among the latter, there are limited data on dental health. We conducted a systematic review with the primary aim of clarifying the extent of the relationship between dental diseases and schizophrenia. The second aim was to delineate an intervention program based on illness-related factors that influence dental health. The preferred reporting items for systematic reviews and meta-analyses statement for reporting systematic reviews was used. Only articles published in English language peer-reviewed journals were considered; we excluded case reports, meta-analyses, and systematic reviews, as well as studies that did not clearly report statistical analysis, diagnostic criteria, or the number of patients included. Twenty-one studies comprising 13,110 patients with schizophrenia and 9025 healthy controls were included. Negative symptomatology, long duration of illness, smoking habit, drug-induced xerostomia, and neuroinflammation are the most critical areas. We suggest an intervention program for prevention and treatment of dental diseases in schizophrenia.

Maternal immune activation and neuroinflammation in human neurodevelopmental disorders.

Maternal health during pregnancy plays a major role in shaping health and disease risks in the offspring. The maternal immune activation hypothesis proposes that inflammatory perturbations in utero can affect fetal neurodevelopment, and evidence from human epidemiological studies supports an association between maternal inflammation during pregnancy and offspring neurodevelopmental disorders (NDDs). Diverse maternal inflammatory factors, including obesity, asthma, autoimmune disease, infection and psychosocial stress, are associated with an increased risk of NDDs in the offspring. In addition to inflammation, epigenetic factors are increasingly recognized to operate at the gene-environment interface during NDD pathogenesis. For example, integrated brain transcriptome and epigenetic analyses of individuals with NDDs demonstrate convergent dysregulated immune pathways. In this Review, we focus on the emerging human evidence for an association between maternal immune activation and childhood NDDs, including autism spectrum disorder, attention-deficit/hyperactivity disorder and Tourette syndrome. We refer to established pathophysiological concepts in animal models, including immune signalling across the placenta, epigenetic 'priming' of offspring microglia and postnatal immune-brain crosstalk. The increasing incidence of NDDs has created an urgent need to mitigate the risk and severity of these conditions through both preventive strategies in pregnancy and novel postnatal therapies targeting disease mechanisms.

Contrasting Roles of the Galectin-3 in the Schizophrenia Onset, Clinical Presentation, and Somatic Comorbidity.

The role of the Galectin-3 (Gal-3) has already been explored in various somatic diseases, considering its engagement in infection, acute and chronic inflammation, and autoimmunity. Additionally, it has been recognized that Gal-3 is included in neuroinflammation and neurodegeneration, so we presented the possibility for its involvement in neuroprogression in schizophrenia. Gal-3 possibly participates in the early life programming of schizophrenia, also in the specific response to viral infections as a "second hit" later in life, and as a part of a unique systemic somatic dysfunction leading to the specific mental changes. In this review, we would like to put all these previous observations of Gal-3 properties in the context of schizophrenia onset, clinical symptoms presentation, frequent somatic comorbid states, and future options for Gal-3 centered treatment in schizophrenia.